Method and device for the removal of partially protein bound substances

ABSTRACT

A method and a device to increase the efficiency of dialysis for the removal from blood of substances that are more or less tightly bound to carriers such as albumin. According to the invention this is accomplished by a simultaneous significant increase of the flow rate of the dialysis fluid and of the area of the membrane that separates the blood from the dialysis fluid, compared to conventional dialysis.

FIELD OF THE INVENTION

This invention relates to a method and a device for increasing theefficiency of dialysis for the removal of substances from a biologicalfluid such as blood, which substances are more or less tightly bound tocarriers such as albumin.

BACKGROUND

For people who have lost all or most of their kidney or liver functions,it is necessary to find alternative ways of cleaning the blood. Onecommon alternative is dialysis, in which the waste products in the bloodare transported across a membrane to a cleaning fluid. In hemodialysis,the most common form of dialysis, blood is removed from the body, and isled to an external device, the dialyzer, which contains a membrane withblood flowing on one side and a dialysis fluid flowing on the other sideof the membrane. The blood is then returned to the body. Due to theconcentration difference between the blood and the dialysis fluid acrossthe membrane, waste products in the blood will be transported bydiffusion to the dialysis fluid. At the same time any excess fluid maybe removed by ultrafiltration, which is achieved by creating a pressuredifference across the membrane.

This dialysis procedure can be very effective for substances that aredissolved in the body fluids, including the blood plasma. The drivingforce for the transport across the membrane is the concentrationdifference, and as long as this concentration difference is maintained,the transport rate can be high. For substances with a zero concentrationin the dialysis fluid, the transport rate can be calculated as theproduct of the blood concentration and a factor known as the dialyzerclearance. The clearance value can be viewed as the fraction of theblood flow that is totally cleared from the substance in question, andis measured in ml/min.

The main determinants for the clearance (Cl) are the flow rates of blood(Q_(b)) and dialysis fluid (Q_(d)), and the transport capacity of themembrane. The membrane can be characterized by its mass transfercoefficient, k_(o)A, which is proportional to the membrane area, and canbe interpreted as the clearance that would be obtained at very largeflow rates of blood and dialysis fluid. An equation for the dialyzerclearance can be derived theoretically by calculating the concentrationprofiles along the dialyzer. Considering a mass balance at each pointalong the dialyzer, taking into account the mass transported by theflows, and the diffusion across the membrane, leads to a set ofdifferential equations for the concentrations along the dialyzer in thedirection of the blood flow. The mass removal rate needed for thecalculation of clearance is then obtained from the blood flow rate andthe calculated change in the blood concentration. In the absence of anyultrafiltration clearance is given by equation 1 $\begin{matrix}{{Cl} = {Q_{b} \cdot \frac{\left( {1 - {\mathbb{e}}^{f}} \right) \cdot Q_{i}}{Q_{d} - {Q_{b} \cdot {\mathbb{e}}^{f}}}}} & (1)\end{matrix}$wherein e denotes the exponential function, and the exponent f iscalculated from equation 2 $\begin{matrix}{f = {k_{a}{A\left( {\frac{1}{Q_{d}} - \frac{1}{Q_{b}}} \right)}}} & (2)\end{matrix}$

For the derivation of equations 1 and 2 it is assumed that both bloodand dialysis fluid are perfectly mixed at each point along the dialyzer.The concentration is thus assumed to vary along the dialyzer accordingto the calculated concentration profiles, but the concentrations areassumed to be independent of the distance from the membrane. It is alsoassumed that the flows are equally distributed in the whole dialyzer.Even with these limitations the equations have been shown in practice towell describe the dependence of clearance on the flow rates of blood anddialysis fluid. These equations, with a correction for ultrafiltrationwhen needed, are therefore often used to describe the capacity ofdialyzers.

A closer study of equations 1 and 2 reveals that the clearance can neverexceed either of Q_(b), Q_(d), or k_(o)A. The dialysis fluid flow rateQ_(d) and the k_(o)A are limited only by the available equipment, butthe blood flow rate is limited by the rate at which blood can beobtained from the blood access in the patient. This is for dialysisnormally in the range 200-500 ml/min. This limits the maximum efficiencythat can be obtained in dialysis treatments, and has lead to fairlystandardized values for Q_(d) and membrane k_(o)A used in normaldialysis treatments, since the cost of higher flow rates and k_(o)Acannot be justified by a better efficiency.

If Q_(d) is increased when Q_(b) and k_(o)A are fixed, clearance willincrease to a certain fraction of the blood flow rate, which isdetermined by k_(o)A. Already at a Q_(d) of twice the blood flow rateclearance is close to this limit, and little is gained by going higher.Dialysis fluid flow rates in standard hemodialysis are thereforenormally in the range 500-800 ml/min.

If instead k_(o)A is increased when Q_(d) and Q_(b) are fixed, clearancewill approach Q_(b) independently of Q_(d) (as long as Q_(d) is higherthan Q_(b) ). The increase is noticeable even at k_(o)A values up to 3-4times the blood flow rate, but for economical and practical reasonsdialyzer k_(o)A values in standard hemodialysis are usually limited tothe range 500-1000 ml/min.

The analysis above is valid for substances that are dissolved in fluidssuch as plasma. But many substances are to a large extent bound tocarriers such as albumin. Examples of substances that can bind toalbumin are butyric and valeric acid, thyroxine, tryptophane,unconjugated bilirubin, mercaptans, and aromatic amino acids. A numberof drugs are known to have a high binding rate to albumin in cases ofaccidental overdosage or suicidal intoxications by e.g. tricyclicantidepressants, digoxin, digitoxin, theophylline or a benzodiazepine.

Hemoglobin may also act as a carrier, e.g. for carbon monoxide orcyanide. These substances have a high affinity to hemoglobin, and willreplace oxygen, which significantly decreases the ability of the bloodto transport oxygen.

In many cases it may be important to have a high removal rate also forsubstances in the blood that to a large extent are bound to proteins orother carriers, such as fungus toxins. But the situation is differentfrom that of the dissolved substances discussed above. Even with a largetotal amount of partly protein bound and partly dissolved substance inthe blood, the plasma concentration may be low, since most of thesubstance may be bound. The concentration gradient across the membranewill then be small, so that the transport rate in dialysis will be low,as will the treatment efficiency.

Previous attempts to solve this problem have focused on adding a carrierto the dialysis fluid as well. For albumin bound toxins, a commonsolution is to add albumin to the dialysis fluid. Substances transportedacross the membrane into the dialysis fluid will then bind to thealbumin in the dialysis fluid. This will keep the concentration low inthe dialysis fluid, so that the transport across the membrane cancontinue without a disappearing concentration gradient. The capacity ofthe dialysis fluid to carry protein bound substances thus becomes muchgreater, see e.g. U.S. Pat. No. 5,744,042.

With most of the substance bound to carriers, the concentration gradientis still small, and even better results may be achieved if the membraneitself is also modified to enhance the transport. This has beensuggested in U.S. Pat. No. 5,744,042, where the membrane is primed withalbumin so that the inner and outer membrane surfaces are covered withalbumin, which adheres to the surfaces. Thus, sites are created withinthe membrane that can act as mediators for the transport across themembrane.

A major disadvantage with adding a carrier like albumin to the dialysisfluid and/or to the membrane is that it is very expensive. It istherefore desirable not to waste this dialysis fluid including albumin.In U.S. Pat. No. 5,744,042 it is suggested to put a cleaning cartridgein the dialysis loop that will remove the bound substances from thecarrier to regenerate the dialysis fluid. By doing so only a smallamount of dialysis fluid is needed since it can be reused over and overagain. The problem is that this fluid will be saturated with all thesolutes that are not removed by the cartridge, and it was thereforenecessary to introduce a second loop of dialysis in order to clean theprimary dialysis fluid, and also to remove any excess fluid that isnormally accumulated in a patient between treatments.

SUMMARY OF THE INVENTION

In prior art, the procedure, thus, becomes expensive and slow as well ascumbersome, and there is a need for a simpler way to remove carrierbound substances from blood. The present invention is based on a morecareful exploration of the mechanisms behind the transport of carrierbound substances across a dialysis membrane.

A theoretical formula for dialyzer clearance can be derived also in thiscase, if we assume that the ratio between the total amount of thesubstance and the amount that is dissolved in plasma is constant. If wedenote this ratio by a, and define clearance as the removal rate dividedby the total concentration in blood (including the fraction that isbound) the formula for clearance becomes modified as shown by equation(3) $\begin{matrix}{{Cl} = {Q_{b} \cdot \frac{\left( {1 - {\mathbb{e}}^{f}} \right) \cdot {Q_{d}/\alpha}}{{Q_{d}/\alpha} - {Q_{b} \cdot {\mathbb{e}}^{f}}}}} & (3)\end{matrix}$

Compared to equation (2) the exponent f is modified as shown in equation(4) $\begin{matrix}{f = {\frac{k_{o}A}{\alpha}\left( {\frac{\alpha}{Q_{d}} - \frac{1}{Q_{b}}} \right)}} & (4)\end{matrix}$

In the derivation of equations 3 and 4 it was assumed that the ratio αis constant over time and in the whole dialyzer. This means that theequilibrium between the carrier bound fraction and the dissolvedfraction is assumed to be instantaneous, so that when material isremoved by dialysis from plasma, a corresponding amount is immediatelyreleased from the carrier. A delay in this process may decrease theresulting clearance, but the decrease can be minimized by variousactions to maximize the residence time of the blood in the dialyzer.

The effect of ultrafiltration is also neglected in equations 3 and 4.For dissolved substances ultrafiltration is known to increase clearanceby about ⅓to ½of the ultrafiltration rate, which usually means anincrease of a few per cent. For carrier bound substances the effect ofultrafiltration is more complicated. Ultrafiltration in itself does notchange the concentration in the remaining blood, and the carrier boundfraction of the substance is therefore unavailable for removal by pureultrafiltration. Another effect of ultrafiltration is to decrease theflow of plasma, which makes it easier to decrease the plasmaconcentration of the substance. At the same time the blood becomes moreconcentrated, so that the concentration of the carrier also increases.This will increase the binding ratio α further, which tends to decreasethe removal. The total effect of ultrafiltration on removal of carrierbound substances is probably less than for non bound substances.

The situation becomes different if the ultrafiltration is preceded bydilution of the blood, as is the case in predilution hemofiltration andhemodiafiltration, the latter being a combination of standardhemodialysis and hemofiltration. When the blood is diluted, theconcentration of dissolved substance becomes lower, and this causes thecarriers to release part of the bound substance. This released substanceis then removed by the subsequent ultrafiltration step, which does notchange the concentration.

It is possible to calculate the efficiency of such a predilutionhemofiltration procedure. The binding ratio α will, however, change whenthe blood is diluted. For the calculation we instead assume that theamount of substance bound to each carrier molecule is proportional tothe concentration of the substance in the surrounding plasma. We alsoassume that the same flow rate of dialysis fluid Q_(d) that is added inthe dilution step is then removed by ultrafiltration. An analysis of theeffect of dilution on the concentrations then shows that clearance inthis case is given by equation 5 $\begin{matrix}{{Cl} = {Q_{b} \cdot \frac{Q_{d}/\alpha}{{Q_{d}/\alpha} + Q_{b}} \cdot Q_{b}}} & (5)\end{matrix}$

For α=1 (no binding) equation 5 agrees with the standard formula forpredilution hemofiltration clearance. The effect of binding is to reducethe influence of the dialysis fluid flow rate by a factor of α. Thisflow rate therefore may have to be increased in order to get asufficient clearance. Since the same flow rate also needs to be removedby ultrafiltration, this increases the demand on the filter to bepermeable to the fluid. The necessary ultrafiltration rate is usuallyobtained by applying a pressure gradient across the membrane. Theultrafiltration rate is proportional to the applied pressure with aproportionality coefficient denoted L_(p)A, which is proportional to themembrane area. To achieve a sufficient ultrafiltration rate at amoderate pressure it is therefore often necessary to increase themembrane area correspondingly.

Equations 3 and 4 show that in hemodialysis the effect on clearance ofthe partial binding of the substance to a carrier can be summarized asboth membrane mass transfer coefficient k_(o)A and dialysis fluid flowrate being divided by the binding ratio α. Since the value of this ratioα may be 10 or much more, the effect on clearance can be so large thatthe effect of the dialysis procedure becomes far too small to be of anypractical value.

For substances dissolved in plasma it is, as discussed above, normallythe blood flow rate Q_(b) that is the limiting factor for clearance, andit is of limited value to increase k_(o)A (or L_(p)A for hemofiltration)or dialysis fluid flow rate Q_(d). But for carrier bound substances withan a above 3-4, equations 3, 4 and 5 show that it is normally no longerthe blood flow rate that is the limiting factor. Instead both k_(o)A (orL_(p)A for hemofiltration) and Q_(d) are limiting and need to beincreased. But it does not help much to increase just one of them, sincethe other one will then still limit the clearance. Instead they bothneed to be increased simultaneously.

Ideally, both k_(o)A (or L_(p)A for hemofiltration) and dialysis fluidflow rate should be increased by a factor of α in order to totallycounteract the effect of the binding to the carrier. In cases where thebinding factor is large, say up to 100, this would however for practicalreasons be difficult to achieve. But usually it is not necessary withsuch a large increase in clearance, since the carrier is normallypresent mainly in the blood, and only to much lesser extent in the restof the body fluids. This means that a large part of the substance isfound in the blood, even though the concentration in other body fluidsmay be the same as in plasma. The apparent total volume of body fluid,i.e. mainly plasma with partially protein bound substances, to becleaned is therefore usually much smaller than the volume of total bodywater with therein dissolved non-protein bound substances. Moreover, thetotal amount of substance (protein bound and dissolved) to be removed issmaller than substances to be removed in normal dialysis, i.e. urea etc.

The dialysis fluid flow rate and the membrane mass transfer coefficientk_(o)A (or L_(p)A for hemofiltration) should be increased at least by afactor of 3-4, but preferably by a factor of 10. Even higher factors areuseful, but a ten-fold increase may often be sufficient, even for highbinding factors above 10 and up to 100. The product of the blood flowrate and the ratio α can be used as a guideline for suitable values ofthe dialysis fluid flow rate and the membrane mass transfer coefficientk_(o)A (or L_(p)A for hemofiltration), but for high binding ratios α,10% of this product may have to suffice.

Since in these cases the blood flow rate often is not the limitingfactor, it may even be possible to lower the blood flow rate. Theimportant factor is still to increase the membrane mass transfercoefficient k_(o)A (or L_(p)A for hemofiltration) and the dialysis fluidflow rate, and the blood flow rate may then be lowered at least down toa fraction of 1/α of the largest of these two. Such an action couldlimit any detrimental effects on the blood vessels that may be caused byremoving large quantities of blood. Thus, patients intoxicated by drugsor other toxins may be treated by the method according to the presentinvention by inserting needles or catheters in a large but superficialblood vessel such as the Vena Cephalica, where a blood flow rate in therange of 50 ml/min can be obtained.

The lower blood flow rate may also increase the efficiency of theprocedure by allowing a longer residence time of the blood in thedialyzer in cases where the equilibrium between the bound and dissolvedfractions of the substances has a time delay. The dialysis fluid flowrate and k_(o)A should still be kept above 2000 ml/min, and preferablyabove 5000 ml/min or even higher. In hemofiltration L_(p)A needs to belarge enough to allow the necessary ultrafiltration rate with the highdialysis fluid flow rate at a moderate pressure gradient.

The membrane area, which is proportional to k_(o)A and L_(p)A, caneasily be increased either by using several standard dialysis filters ina series or in a parallel configuration, or combinations thereof, or byusing specially designed filters with increased membrane area.

To increase the dialysis fluid flow rate requires some furtherconsiderations. The production of, say, 5 liters per minute of dialysisfluid puts high demands on the supply of water, which has to be of ahigh quality.

The dialysis fluid also has to contain electrolytes like Sodium,Potassium, Calcium, Chloride and Bicarbonate in concentrations thatcorrespond to those of blood. This is in normal dialysis achieved bymixing the water with concentrated solutions of these ions. With thelarge amount of fluid required for the present invention the requiredamount of concentrate will also be large. The handling of these largequantities could be significantly simplified if one or more of theelectrolytes are supplied in dry form as suggested in U.S. Pat. No.4,784,495. Another method to handle this problem is to use a largecentral mixing station to prepare the dialysis fluid, which is thenpumped through delivery lines to the place of use.

One way to decrease the large demand for water and concentrates is toregenerate the spent dialysis fluid by an ultrafiltration process. Afilter with a high permeability for water, and with a suitable pore sizeto allow the electrolytes to pass, but not the substances that are to beremoved, is placed in the spent dialysis fluid. The ultrafiltrate isreused, and the now concentrated spent dialysis fluid is wasted. Thisprocess is possible to use in cases where the substances to be removedare sufficiently larger than the electrolytes.

Furthermore, the dialysis fluid has to have a temperature that is closeto normal body temperature. The dialyzer will act as a heat exchangerbetween blood and the dialysis fluid. If the dialysis fluid is cold theblood that is returned to the patient will have a too low temperature,which will cause discomfort. In normal dialysis treatments all of thedialysis fluid is heated to around 38° C. The power required for heatinga dialysis flow rate of 500-800 ml/min is at the limit of what astandard wall outlet can produce. For the higher end of the flow ratesit may not even be sufficient, especially if the incoming water isparticularly cold. In such cases a heat exchanger is often used totransfer heat from the spent dialysis fluid to the incoming water.

For the present invention there is needed a dialysis flow rate that maybe 10 times higher than normal. Even a heat exchanger is then notsufficient to allow the total amount of dialysis fluid to besufficiently heated by the power available in a standard wall poweroutlet. Performing the main part of the procedure using unheateddialysis fluid can solve this problem. The blood can then be heated justbefore it is returned. This can be done e.g. using a blood heater thatacts on the outside of the blood line.

Another possibility is to heat a small fraction of the total amount ofdialysis fluid. The system should then be arranged so that the unheatedportion of the dialysis fluid is used first, and the final heatedfraction of the dialysis fluid is used for the final treatment of theblood just before it is returned to the patient.

The use of unheated dialysis fluid for the major part of the procedure,and the consequent lowering of the blood temperature, might affect theefficiency. It is well known that the effect of diffusion decreases whenthe temperature is decreased, but temperature may also affect thebinding ratio α. Various carrier/toxin combinations may reactdifferently in this respect. The efficiency of the procedure willdecrease if a increases.

An alternative method to handle the heating problem is to use a centralmixing station for both the preparation and heating of the dialysisfluid. The whole procedure may then be performed at an elevatedtemperature in cases where this may be important for efficiency reasons.Warm dialysis fluid with the correct composition of water andelectrolytes is then distributed from a central mixing station to eachof the sites where the dialysis machines are situated.

In order to achieve the effect of a larger clearance of carrier boundsubstances it is necessary to address both issues of membrane area andflow of dialysis fluid. As disclosed in the present invention this canbe done by making both membrane area and dialysis fluid flow rate large.In U.S. Pat. No. 5,744,042 both factors are instead handled by addingthe carrier albumin. These two approaches could also be combined. Acarrier, such as albumin, could be added to the dialysis fluid, but notto the membrane, which instead is made large as described above.Alternatively, the membrane is primed with albumin, but no carrier isadded to the dialysis fluid, which instead is supplied in a largeamount.

In a further embodiment of the present invention a carrier such asalbumin is added to the large dialysis fluid flow and the large membraneis primed with the same or other carrier. The carrier is e.g. serumalbumin. The concentration of serum albumin is preferably above 10 g/l.This embodiment of the invention is advantageous where very stronglybound substances are to be removed or where a ratio between bound anddissolved substances is exceptionally high.

In still a further embodiment of the invention a large dialysis fluidflow rate of about 4000 ml/min could be combined with a large membranehaving a K_(o)A of about 4000 ml/min and a concentration of a carriersuch as serum albumin which is about 5 g/l. This embodiment isadvantageous as the concentration of expensive albumin is limited whilethe effect of the dialysis treatment is kept on an acceptable level.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram, which schematically shows a dialysis systemto carry out the invention.

FIG. 2 is a block diagram showing an alternative arrangement ofdialyzers.

FIG. 3 is a block diagram showing yet another arrangement of dialyzers.

FIG. 4 is a block diagram, which schematically shows an alternativedialysis system to carry out the invention.

FIG. 5 is a block diagram, which schematically shows yet anotherdialysis system to carry out the invention.

FIG. 6 is a block diagram, which schematically shows a predilutionhemofiltration system to carry out the invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

A first embodiment of the invention is shown in FIG. 1, whichschematically shows a system with a close resemblance to a standardsystem for hemodialysis. Blood is transported with the help of a pump 10from the patient via an arterial blood line 11 through the bloodcompartment 21 of a large dialyzer 20, and then via blood line 15 intothe blood compartment 31 of a smaller dialyzer 30. It is then returnedto the patient via blood line 17. Semipermeable membranes 22 and 32 indialyzers 20 and 30, respectively, separate the blood compartments 21and 31, respectively, from the dialysate compartments 23 and 33,respectively.

The pore size of the semipermeable membranes 22 and 32 should be chosenlarge enough to allow the passage of the toxins that are to be removed,the size of which in some cases are several thousand Daltons. Themembranes should, on the other hand, effectively prevent the passage ofcarriers such as albumin, which has a size of about 66000 Daltons. Theserequirements can be fulfilled by membranes made from e.g. polysulfones,polyamides, polycarbonates, polyesters, acrylonitrile polymers, vinylalcohol polymers, acrylate polymers, methacrylate polymers or celluloseacetate polymers.

For the preparation of a dialysis fluid, clean water obtained from aclean water plant conventionally used in dialysis treatments enters thewater inlet 50, and is then mixed to the correct composition in twosteps. In the first step a concentrate pump 60 delivers a concentratedsolution of Chlorides of Sodium, Potassium, Calcium and Magnesiumtogether with an acid, such as Acetic acid, Hydrochloric acid or Citricacid, from a container 61 via concentrate lines 62 and 63 to a mixingpoint 65 in the main fluid line 51. The conductivity of the mixture ismeasured in a conductivity cell 66. The measured conductivity isregistered in a control unit (not shown), and is compared to the desiredvalue. The control unit controls the speed of the concentrate pump 60 sothat the conductivity is kept at the desired value.

In the second mixing step a concentrate pump 70 delivers a concentratedsolution of Sodium Bicarbonate from a container 71 via concentrate lines72 and 73 to a mixing point 75 in the main fluid line 51. Theconductivity of the mixture is measured in a conductivity cell 76. Themeasured conductivity is registered in the control unit (not shown), andis compared to the desired value. The control unit controls the speed ofthe concentrate pump 70 so that the total conductivity is kept at thedesired value.

The dialysate flow then passes a restrictor 80, with the flow ratemaintained by a pump 90 in the main fluid line. The effect of therestrictor 80 is to allow a sufficiently low dialysate pressure in thedialyzers, so that a sufficient amount of fluid can be retracted fromthe blood by the process of ultrafiltration through the semipermeablemembranes 22 and 32, irrespectively of the pressure on the blood side.The flow rate is measured in a flow cell 100, and the measured value isregistered in a control unit (not shown) that will control the speed ofpump 90 so that the desired fluid flow rate is achieved.

The main fraction of the flow is then directed through line 110 forfurther transport via valve 150 and lines 112 and 113 directly to thedialysate compartment 23 of the large dialyzer 20. The rest of the flowis directed through line 111 to a heater 120, an adjustable restrictor130 and a flow meter 145. The heater 120 will heat the fluid to sometemperature below 40° C. as measured by a not shown temperature sensor.This temperature is chosen to give the blood that leaves dialyzer 30 asuitable temperature. The adjustable restrictor 130 is designed toassure that only about 500 ml/min of the flow, as measured by the flowmeter 145, passes this way, and may be adjustable to allow for this partof the flow to stay the same even though the main flow may be differentat different occasions. If the temperature and the composition of theflow are correct the three way valve 140 may be set to allow the flow tocontinue through line 114 to the dialysate compartment 33 of the smallerdialyzer 30. After passing dialyzer 30 this flow will continue throughline 113 where it will meet the main fraction of the flow, and all ofthe flow will pass dialyzer 20 and continue through line 115.

If the dialysis fluid does not fulfill the requirements, e.g. ontemperature or composition, or if for some other reason no dialysateflow is wanted in the dialyzers, the control unit will set the three wayvalves 140 and 150 to direct the fluid through bypass lines 141 and 151,respectively, and the direct lines 112 and 114 respectively will beclosed off. All of the dialysate fluid will then go directly to line 115without passing the dialyzers, and this will guarantee that any blood inthe dialyzers cannot be damaged by dialysis fluid that does not have thecorrect composition or temperature.

The spent dialysis fluid is then led to a second flow cell 101, wherethe flow rate is measured and is registered by the control unit. Thedifference of the accumulated flows registered in flow cells 100 and 101will be a measure of the volume that has been ultrafiltered from theblood. The control unit will adjust this volume to a desired value bycontrolling the speed of pump 170, which controls the flow rate of thespent dialysate. The effect of the restrictor 180 is to allow positivepressures in the dialysate compartments 23 and 33 in order to limit theultrafiltration in cases where the pressure on the blood side is high.Also shown is a blood leak detector 160 designed to detect also smallleakages of blood into the dialysis fluid. Should this occur, the bloodleak detector will send a signal to the control unit, which willactivate the three way valves 140 and 150 so that the dialysis fluidbypasses the dialyzers, and the blood pump 10 is stopped. Other actionsmay also be initiated, such as emitting an alarm signal.

Only parts that are relevant to the present invention have been includedin the description above. Several other features may be necessary for asuccessful operation of the system, but are well known from standarddialysis machines. Such well known features include, but are not limitedto, degassing of the dialysis fluid before the dialyzers, doublemeasurements of a number of essential parameters to obtain doublesafety, measurement of the pH of the dialysis fluid, clamps on the bloodlines that make it possible to seal off the dialyzers from the rest ofthe blood lines, and a drip chamber with an air detector in the venousblood line 17.

To a large degree the system is set up and controlled much like astandard system for hemodialysis. The small dialyzer 30 may be astandard filter for hemodialysis, but the large dialyzer 20 shown inFIG. 1 is much larger. Depending on the substances that are to beremoved it may have a membrane area in the range 8-10 m² or larger,resulting in a k_(o)A value of 4000 ml/min or larger. For substancesthat are tightly bound to their carriers, i.e. substances with a largevalue of α, the k_(o)A value needs to be large. The upper limit is setmainly by practical and economical limitations.

At startup, the blood lines are supplied with a priming solution, suchas physiological saline solution, and the control unit performs a numberof safety tests before the correct settings are put into effect for theconductivities, the temperature in the heater and the dialysis fluidflow rates.

According to the invention the main flow rate of the dialysis fluid hasto be much larger than for normal hemodialysis. Depending on thesubstances that are to be removed it should be 2 l/min or higher,preferably 5 l/min or higher, but with no upper limit other thandictated by practical and economical circumstances. The chosen main flowrate is transferred to the control unit, which will then control thepump 90 so that flow cell 100 measures this value. The restrictor 130may then have to be adjusted so that the heated flow rate as shown byflow meter 145 is close to 500 ml/min.

When all tests have been performed and all parameters are controlled totheir correct values blood is introduced into the blood line 11, and thethree way valves 140 and 150 are set to allow the dialysis fluid to passthrough the dialyzers 20 and 30. The dialysis is continued until therequired amount of the substance has been removed. The time requiredwill depend on the parameters of the dialysis and the binding ratio α.If it is possible to obtain a high blood flow rate, so that a highclearance of a few hundred ml/min can be reached, it may be possible toremove up to 90% of a substance with a in the range 5-10 in 30-60minutes because of the efficient removal rate. This may be important incases of acute poisoning. In other cases, where the binding ratio α ismuch higher, and a high blood flow rate does not help, the treatment mayhave to continue for several hours or up to a day.

In an alternative embodiment, the large dialyzer 20 is replaced by anumber of smaller dialyzers, which may each be a standard filter forhemodialysis. FIG. 2 shows a configuration with two arms in parallel,each with two dialyzers in series, both on the blood side and on thedialysis fluid side. The incoming blood line 11 is split up into twolines, each of which goes into one arm with two dialyzers in series. Thetwo blood lines coming out from the two arms are then joined again inblood line 15, which leads to the small dialyzer 30. In a correspondingmanner, the fluid line 113 is split up into two lines, each of whichgoes into one of the two arms with two dialyzers in series. All of thespent dialysis fluid is then collected in line 115.

Any number of dialyzers, and any combination of series and parallelconfigurations is possible. The configurations need not even be the sameon the blood side and the dialysis fluid side. For example, the bloodside of all dialyzers may be arranged in series, while the dialysisfluid side may be arranged in parallel, as shown in FIG. 3 with 3dialyzers. The series configuration has the disadvantage of creating ahigher pressure drop, whereas in the parallel configuration the flowrate will be lower, which may give a decreased performance due toinsufficient filling of the dialyzers. A combination of series andparallel arrangement, as shown in FIG. 2, is therefore preferred.

In yet another embodiment shown in FIG. 4 the dialysis fluid comes tothe system ready to use from a central mixing system. Since all of thedialysis fluid may then already be at almost the correct temperaturethere is no need to separate the dialysis fluid into a cold part and aheated part, and it is possible to use only one large dialyser. Similarto FIG. 1 blood is transported with the help of a pump 10 via anarterial blood line 11 through the blood compartment 21 of a largedialyzer 20 and is then returned via blood line 17. An optional bloodheater 18 may be attached to blood line 17 to heat the blood before itis returned. Such a heater may e.g. transfer heat to the outside of ablood line that is wound around the heater, and may have a capacity toperform all the heating of the blood that is necessary. This would allowthe use of dialysis fluid that has not been heated, and heater 85 couldthen be omitted. The semipermeable membrane 22 in the dialyzer 20separates the blood compartment 21 from the dialysate compartment 23.

The fluid enters the system at the fluid inlet 50 and is transportedthrough line 51 to a heater 85. Even though the fluid should have almostthe desired temperature when it enters the system, there may be a needfor a final small adjustment. The composition of the fluid as reflectedin its conductivity is checked in the conductivity cell 76. The functionof restrictor 80, pump 90 and flow cell 100 is the same as in FIG. 1,i.e. to allow a sufficiently low pressure in the dialysis fluidcompartment for an adequate ultrafiltration to take place, and tomeasure and maintain the flow rate at a desired level.

The flow is then under normal conditions directed through the three wayvalve 140 and line 114, past the flow meter 145 to the dialysis fluidcompartment 23 of the dialyzer 20, which it leaves through line 115. Incase some problems occurs that might lead to unwanted effects on theblood in the dialyzer, a control unit (not shown) will set the three wayvalve to bypass the fluid through line 141 instead of through thedialyzer.

The spent dialysis fluid is then led to a second flow cell 101, wherethe flow rate is measured and is registered by the control unit. Thedifference of the accumulated flows registered in flow cells 100 and 101will be a measure of the volume that has been ultrafiltered from theblood. The control unit will adjust this volume to a desired value bycontrolling the speed of pump 170, which controls the flow rate of thespent dialysate. The effect of the restrictor 180 is to allow a positivepressure in the dialysate compartment 23 in order to limit theultrafiltration in cases where the pressure on the blood side is high.Also shown is a blood leak detector 160 designed to detect also smallleakages of blood into the dialysis fluid. Should this occur, the bloodleak detector will send a signal to the control unit, which willactivate the three way valve 140 so that the dialysis fluid bypasses thedialyzer, and the blood pump 10 is stopped.

Again, only parts that are relevant to the current invention have beenincluded in the description above. Several other features, e.g. thoselisted in connection with FIG. 1, may be necessary for a successfuloperation of the system, but are well known from standard dialysismachines. Variations and combinations of features described above arealso possible. Instead of one large dialyzer as shown in FIG. 4 it ispossible to use various combinations of smaller, standard dialyzers asshown in FIG. 2 and FIG. 3.

In a different embodiment of the invention, also shown in FIG. 4, thesame large flow of dialysis fluid is used as discussed above, but themembrane 22 of the filter 20 has been coated with albumin in apretreatment as disclosed in U.S. Pat. No. 5,744,042. The flow rate ofdialysis fluid needs to be above 2 l/min, preferably above 5 l/min, andat least 10 times the blood flow rate, but with such a membrane coatingthe membrane area no longer needs to be large. The coating of themembrane can be done long before the use of the filter, which can then,under suitable conditions, be stored for many months. Another method isto use a standard synthetic membrane, such as a polyamide or polysulfonemembrane, which, just before starting the treatment, is primed with asaline solution containing albumin in a concentration above 10 g/l, orpreferably above 40 g/l and more preferably above 70 g/l. Priming isperformed by directing the solution past one or both sides of themembrane with the help of the pumps in the system.

The dialysis fluid in FIG. 4 is delivered from a central mixing station.Alternatively it can also in this embodiment be prepared locally asshown in FIG. 1.

FIG. 5 shows an embodiment where a dialyzer 20 with the same largesurface area as discussed above is used, but the carrier albumin isadded to the dialysis fluid. The concentration of albumin should beabove 10 g/l, preferably above 40 g/l and more preferably above 70 g/l.The addition of albumin to the dialysis fluid increases its transportcapacity of protein bound substances so that it is no longer necessaryto increase the flow rate above conventionally used flow rates of500-1000 ml/min. To counteract completely the effect of protein binding,the membrane area in dialyzer 20 should preferably be increased by afactor CL above what would normally be used. In practise, this may beimpractical or too costly to achieve, and smaller areas may have tosuffice. In any case, k_(o)A needs to be at least 5 times the blood flowrate, preferably 10 times the blood flow rate, or above 2000 ml/min,preferably above 4000 ml/min, for the membrane to have an acceptabletransport capacity.

In order to minimize the consumption of albumin, the albumin containingdialysis fluid is circulated in a closed loop in the embodiment shown inFIG. 5. Blood pump 10 delivers blood from the patient into the bloodcompartment 21 of the large dialyzer 20, and the blood is returned tothe patient via line 17 and an optional blood warmer 18.

The albumin containing dialysis fluid is circulated through thedialysate compartment 23 by pump 170. A blood leak detector 160 and abubble separator 190 are also placed in line 115. The dialysis fluidthen passes the blood compartment 31 of a second dialyzer 30, which isof conventional type. By connecting the dialysate side 33 to aconventional dialysis machine 200 this dialyzer will remove water andwaste products like urea and creatinine that are dissolved in thedialysis fluid. The dialysis fluid then passes two adsorption columns210 and 220 before it is returned to dialyzer 20.

Columns 210 and 220 contain material with a high affinity for theprotein bound substances that are bound to albumin in the dialysisfluid. These substances will therefore be trapped in the columns, andthe albumin in the dialysis fluid is again free to act as carrier to newmolecules in dialyzer 20. Columns 210 and 220 may e.g. be charcoaladsorbent columns like the Adsorba 300 C from Gambro AB or N350 fromAsahi, and/or an anion exchange column like BR350 from Asahi. The numberof columns required and their types may depend on the substance orsubstances that are to be removed.

In cases e.g. poisoning where no removal of completely dissolved wasteproducts and water is required, i.e. only protein bound substances needto be removed, dialyzer 30 and dialysis machine 200 are not needed, andcan be left out. Also, the columns 210 and 220 may be left out if theamount of albumin present in the dialysis loop is sufficient to carrythe total amount of protein bound substances that is to be removed.Various configurations can thus be conceived within the scope of thisembodiment.

Alternatively the embodiment shown in FIG. 5 comprises a large surfacearea dialyser 20 of the same type as disclosed in FIG. 4 that is coatedwith a carrier, e.g. albumin.

The embodiment shown in FIG. 6 is adapted to carry out the inventionusing predilution hemofiltration, which is performed with blood anddialysate in a cocurrent configuration, i.e. the blood and theultrafiltered dialysate flow in the same direction in the dialyzer.Similar to FIG. 4 blood is transported with the help of a pump 10 via anarterial blood line 11 through the blood compartment 21 of a largedialyzer 20 and is then returned via blood line 17. An blood heater 18may be attached to blood line 17 to heat the blood before it isreturned.

The dialysis fluid enters the system at 50, and is treated exactly as inFIG. 1 until it leaves the flow cell 100. The flow is then under normalconditions directed through the three way valve 140 and line 122 tocompartment 43 of the ultrafilter 40. In case some problems occurs thatmight lead to unwanted effects on the blood in the dialyzer, a controlunit (not shown) will set the three way valve to bypass the fluidthrough line 141 instead of through the ultrafilter.

A pump 135 will be adjusted by a control unit (not shown) to deliver theexact flow of dialysis fluid required from compartment 41 of theultrafilter, through line 124 to mixing point 12, where the dialysisfluid and the blood are mixed before entering dialyzer 20. Any unuseddialysis fluid will leave compartment 43 through line 123, and thisfluid together with the ultrafiltrate from compartment 23 of dialyzer 20will be directed through line 115, flow cell 101, blood leak detector160 and restrictor 180 by pump 170. The control of this part of thesystem is identical to that of FIG. 1.

The embodiments shown above are only examples of how the invention couldbe carried out, and other embodiments are possible for large or smallparts of the system. The large quantities of dialysis fluid needed wille.g. require large quantities of electrolyte concentrates supplied inthe containers 70 and 71 of FIG. 1. The handling of these largequantities could be significantly simplified if one or more of theelectrolytes are supplied in dry form as suggested in U.S. Pat. No.4,784,495. Also, for the control of ultrafiltration, the use of pump 170and flow cells 100 and 101 could be replaced by a system with balancingchambers and a separate ultrafiltration pump as described in U.S. Pat.No. 4,267,040 or similar. In FIG. 4, the dialysis fluid does not have tobe preheated, and heater 85 is not needed, if the blood before beingreturned is instead heated by a blood warmer attached directly to line17. This principle can of course also be applied if the dialysis fluidis prepared in the machine as shown in FIG. 1, and there is then no needto split the fluid into a heated and a non heated part. In FIG. 6 itwould e.g. be possible to use centrally prepared dialysis fluid as inFIG. 4, several smaller dialyzers similar to FIGS. 2 and 3, or a finaldialyzer instead of heater 18 for the heating of the blood.

1. A method for removing partially carrier bound substances from bloodcomprising a blood circuit, a fluid circuit and a filter having asemipermeable membrane separating a fluid compartment from a bloodcompartment, where blood is directed through the blood compartment and acleaning fluid is directed through the fluid compartment characterizedin that a mass transfer coefficient k_(o)A of the filter is at least2000 ml/min; a ratio between the mass transfer coefficient k_(o)A of thefilter and a blood flow rate is at least 5; a cleaning fluid flow rateis at least 2000 ml/min; and a ratio between the cleaning fluid flowrate and the blood flow rate is at least
 5. 2. A method according toclaim 1 where the ratio between the mass transfer coefficient k_(o)A ofthe filter and the blood flow rate is at least 10; and the ratio betweenthe cleaning fluid flow rate and the blood flow rate is at least
 10. 3.A method according to claim 1 or 2 where the mass transfer coefficientk_(o)A of the filter is at least 5000 ml/min; and the cleaning fluidflow rate is at least 5000 ml/min.
 4. A method according to claim 1, 2or 3 where the parameters are chosen in relation to the product of ablood flow rate Q_(b) and a factor a denoting the total amount ofsubstance to be removed in relation to the fraction dissolved in plasmaand the mass transfer coefficient k_(o)A of the filter is at least 10%of this product; and the cleaning fluid flow rate is at least 10% ofthis product.
 5. A method according to claim 4 where the mass transfercoefficient k_(o)A of the filter is at least 100% of this product;and/or the cleaning fluid flow rate is at least 100% of this product. 6.A method for removing partially carrier bound substances from bloodcomprising a blood circuit, a fluid circuit and a filter having asemipermeable membrane separating a fluid compartment from a bloodcompartment, where blood is directed through the blood compartment and acleaning fluid is directed through the fluid compartment characterizedin that a mass transfer coefficient k_(o)A of the filter is at least2000 ml/min; a ratio between the mass transfer coefficient k_(o)A of thefilter and a blood flow rate is at least 5; and the cleaning fluidcontains a carrier that is able to bind the partially carrier boundsubstances in the blood.
 7. A method for removing partially carrierbound substances from blood comprising a blood circuit, a fluid circuitand a filter having a semipermeable membrane separating a fluidcompartment from a blood compartment, where blood is directed throughthe blood compartment and a cleaning fluid is directed through the fluidcompartment characterized in that the membrane has been pretreated witha fluid containing a carrier that is able to bind the partially carrierbound substances in the blood; a cleaning fluid flow rate is at least2000 ml/min; and a ratio between the cleaning fluid flow rate and theblood flow rate is at least
 10. 8. A method according to claim 6 wherethe membrane has been pretreated with a fluid containing a carrier thatis able to bind the partially carrier bound substances in the blood. 9.A method according to claim 7 where the cleaning fluid contains acarrier that is able to bind the partially carrier bound substance inthe blood.
 10. A method according to any of claims 6, 7, 8 or 9 wherethe carrier is serum albumin.
 11. A method according to claim 10 wherethe concentration of the serum albumin is above 10 g/l.
 12. A method forremoving partially carrier bound substances from blood comprising ablood circuit, a fluid circuit and a filter having a semipermeablemembrane separating a fluid compartment from a blood compartment, wherea mixture of blood and a cleaning fluid is directed through the bloodcompartment and a pressure gradient is applied across the membrane tocreate an ultrafiltration into the fluid compartment equal in size tothe sum of a flow rate of the cleaning fluid and a desired weight lossrate of a patient characterized in that a water permeability coefficientL_(p)A of the filter is at least 10 ml/min/mm Hg; the cleaning fluidflow rate is at least 1000 ml/min; and a ratio between the cleaningfluid flow rate and a blood flow rate is at least
 5. 13. A methodaccording to any of claims 1-12, where the filter is replaced by severalfilters arranged in series or parallel, or a combination thereof.
 14. Amethod according to any of claims 1-13 where the blood is heated beforebeing returned to the patient.
 15. A method according to claim 14 wherethe heating is performed in a final dialyzer along a blood path beforethe blood is returned to the patient.
 16. A device adapted to removepartially carrier bound substances from blood comprising a bloodcircuit, a fluid circuit and a filter having a semipermeable membraneseparating a fluid compartment from a blood compartment, where blood isdirected through the blood compartment and a cleaning fluid is directedthrough the fluid compartment characterized in that a mass transfercoefficient k_(o)A of the filter is at least 2000 ml/min; a ratiobetween the mass transfer coefficient k_(o)A of the filter and a bloodflow rate is at least 5; a cleaning fluid flow rate is at least 2000ml/min; and a ratio between the cleaning fluid flow rate and the bloodflow rate is at least
 5. 17. A device according to claim 16 where theratio between the mass transfer coefficient k_(o)A of the filter and theblood flow rate is at least 10; and the ratio between the cleaning fluidflow rate and the blood flow rate is at least
 10. 18. A device accordingto claim 16 or 17 where the mass transfer coefficient k_(o)A of thefilter is at least 5000 ml/min; and the cleaning fluid flow rate is atleast 5000 ml/min.
 19. A device according to claim 16, 17 or 18 wherethe parameters are chosen in relation to the product of a blood flowrate Q_(b) and a factor a denoting the total amount of substance to beremoved in relation to the fraction dissolved in plasma and the masstransfer coefficient k_(o)A of the filter is at least 10% of thisproduct; and the cleaning fluid flow rate is at least 10% of thisproduct.
 20. A device according to claim 19 where the mass transfercoefficient k_(o)A of the filter is at least 100% of this product;and/or the cleaning fluid flow rate is at least 100% of this product.21. A device adapted to remove partially carrier bound substances fromblood comprising a blood circuit, a fluid circuit and a filter having asemipermeable membrane separating a fluid compartment from a bloodcompartment, where blood is directed through the blood compartment and acleaning fluid is directed through the fluid compartment characterizedin that a mass transfer coefficient k_(o)A of the filter is at least2000 ml/min; a ratio between the mass transfer coefficient k_(o)A of thefilter and a blood flow rate is at least 5; and the cleaning fluidcontains a carrier that is able to bind the partially carrier boundsubstances in the blood.
 22. A device adapted to remove partiallycarrier bound substances from blood comprising a blood circuit, a fluidcircuit and a filter having a semipermeable membrane separating a fluidcompartment from a blood compartment, where blood is directed throughthe blood compartment and a cleaning fluid is directed through the fluidcompartment characterized in that the membrane has been pretreated witha fluid containing a carrier that is able to bind the partially carrierbound substances in the blood; a cleaning fluid flow rate is at least2000 ml/min; and a ratio between the cleaning fluid flow rate and theblood flow rate is at least
 10. 23. A device according to claim 21 wherethe membrane has been pretreated with a fluid containing a carrier thatis able to bind the partially carrier bound substances in the blood. 24.A device according to claim 22 where the cleaning fluid contains acarrier that is able to bind the partially carrier bound substances inthe blood.
 25. A device according to any of claims 21, 22, 23 or 24where the carrier is serum albumin.
 26. A device according to claim 25where the concentration of the serum albumin is above 10 g/l.
 27. Adevice adapted to remove partially carrier bound substances from bloodcomprising a blood circuit, a fluid circuit and a filter having asemipermeable membrane separating a fluid compartment from a bloodcompartment, provided with means for mixing blood and a cleaning fluidand directing said mixture through the blood compartment, and means toapply a pressure gradient across the membrane to create anultrafiltration into the fluid compartment equal in size to the sum of aflow rate of the cleaning fluid and a desired weight loss rate of thepatient characterized in that a water permeability coefficient L_(p)A ofthe filter is at least 10 ml/min/mm Hg; the cleaning fluid flow rate isat least 1000 ml/min; and a ratio between the cleaning fluid flow rateand a blood flow rate is at least
 5. 28. A device according to any ofclaims 16-27, where the filter is replaced by several is filtersarranged in series or parallel, or a combination thereof.
 29. A deviceaccording to any of claims 16-28 where a heater is arranged for heatingthe blood before it is returned to the patient.
 30. A device accordingto claim 29 where the heater is a final dialyzer along the blood pathbefore the blood is returned to the patient.